The tumor-suppressor gene Nkx2.8 suppresses bladder cancer proliferation through upregulation of FOXO3a and inhibition of the MEK/ERK signaling pathway
The tumor-suppressor gene Nkx2.8 suppresses bladder cancer proliferation through upregulation of FOXO3a and inhibition of the MEK/ERK signaling pathway
复制标题
肿瘤抑制基因 Nkx2.8 通过上调 FOXO3a 和抑制 MEK/ERK 信号通路来抑制膀胱癌增殖
DOI：
10.1093/carcin/bgr321
复制
发表时间：
2012-03-01
期刊：
影响因子：
4.7
通讯作者：
Song, Libing
中科院分区：
文献类型：
--
作者：
Yu, Chunping;Zhang, Zhiling;Song, Libing
浸润性膀胱癌是一种致死性疾病，其有效的预后标志物以及潜在的治疗靶点仍然缺乏。Nkx2.8（Nk 2 homeobox 8）是NK-2基因家族的新成员，在人类肿瘤的发生发展中起重要作用。在此，我们报道了Nkx2.8在膀胱癌组织中与匹配的邻近正常尿路上皮组织相比显著降低。Nkx2.8水平与晚期T分型、N分型、肿瘤多样性、高增殖指数（Ki-67）和患者生存不良呈负相关。此外，我们发现膀胱癌细胞中Nkx2.8的过表达在体外和体内显著抑制细胞增殖，而沉默Nkx2.8显著增强细胞增殖。此外，我们证明Nkx2.8的过表达导致G（1）/S期阻滞，伴随着p27（Kip 1）的上调，cyclin D1和p-FOXO 3a的下调以及MEK/ERK通路活性的抑制。同时，沉默Nkx2.8可导致G1/S转换加快，p27（Kip 1）表达下调，cyclin D1和p-FOXO 3a表达上调，MEK/ERK通路活性增加。这些发现表明，Nkx2.8在膀胱癌进展中起着潜在的肿瘤抑制作用，并代表了这种疾病的有价值的临床预后标志物。
Invasive bladder cancer is a lethal disease for which effective prognostic markers as well as potential therapy targets are still lacking. Nkx2.8 (Nk2 homeobox 8), a novel member of the NK-2 gene family, was reported to play an important role in the development and progression of human cancer. Herein, we reported that Nkx2.8 was markedly reduced in bladder cancer tissues compared with matched adjacent normal urothelial tissues. Nkx2.8 levels were inversely correlated with advanced T classification, N classification, tumor multiplicity, high proliferation index (Ki-67) and poor survival of patients. Furthermore, we found that overexpression of Nkx2.8 in bladder cancer cells significantly inhibited cell proliferation in vitro and in vivo, whereas silencing Nkx2.8 dramatically enhanced cell proliferation. Moreover, we demonstrated that overexpression of Nkx2.8 resulted in G(1)/S phase arrest, accompanied by upregulation of p27(Kip1), downregulation of cyclin D1 and p-FOXO3a and inhibition of MEK/ERK pathway activity. Meanwhile, silencing Nkx2.8 led to acceleration of G(1)/S transition, downregulation of p27(Kip1), upregulation of cyclin D1 and p-FOXO3a and increase of MEK/ERK pathway activity. These findings suggest that Nkx2.8 plays a potential tumor suppressor role in bladder cancer progression and represents a valuable clinical prognostic marker of this disease.